Endocrinology Commons^™

Staying Sane In The Membrane: Neutral Sphingomyelinase 2 As A Master Regulator Of Plasma Membrane Ceramide, Zainuddin Quadri, Erhard Bieberich

Markey Cancer Center Faculty Publications

Ceramide, a key signaling sphingolipid in the plasma membrane, plays a pivotal role in fundamental cellular processes such as adhesion, polarity, and programmed cell death. The generation of plasma membrane ceramide is largely attributed to the activity of two types of sphingomyelinases: neutral sphingomyelinase 2 (nSMase2, Smpd3) and acid sphingomyelinase (aSMase, Smpd1). While many studies have explored ceramide generation following experimental activation of these enzymes, the mechanisms governing basal or steady- state ceramide levels have remained poorly understood. Using an innovative mass spectrometry approach developed in the Canals’ lab, the team has quantified the distinct contributions of nSMase2 and aSMase …

Bilirubin Bioconversion To Urobilin In The Gut-Liver-Kidney Axis: A Biomarker For Insulin Resistance In The Cardiovascular-Kidney-Metabolic (Ckm) Syndrome, Zachary A. Kipp, Olufunto O. Badmus, David E. Stec, Brantley Hall, Terry D. Hinds Jr.

Markey Cancer Center Faculty Publications

The rising rates of obesity worldwide have increased the incidence of cardiovascular disease (CVD), making it the number one cause of death. Higher plasma bilirubin levels have been shown to prevent metabolic dysfunction and CVD. However, reducing levels leads to deleterious outcomes, possibly due to reduced bilirubin half-life that escalates the production of its catabolized product, urobilinogen, produced by gut bacteria and naturally oxidized to urobilin. Recent findings suggest that the involvement of the microbiome catabolism of bilirubin to urobilin and its absorption via the hepatic portal vein contributes to CVD, suggesting a liver-gut axis involvement. We discuss the studies …

Apoa2 Increases Cholesterol Efflux Capacity To Plasma Hdl By Displacing The C-Terminus Of Resident Apoa1, Snigdha Sarkar, Jamie Morris, Youngki You, Hannah Sexmith, Scott E. Street, Stephanie M. Thibert, Isaac K. Attah, Chelsea M. Hutchinson Bunch, Irina V. Novikova, James E. Evans, Amy S. Shah, Scott M. Gordon, Jere P. Segrest, Karin E. Bornfeldt, Tomas Vaisar, Jay W. Heinecke, W. Sean Davidson, John T. Melchior

Saha Cardiovascular Research Center Faculty Publications

Abstract The ability of high-density lipoprotein (HDL) to promote cellular cholesterol efflux is a more robust predictor of cardiovascular disease protection than HDL-cholesterol levels in plasma. Previously, we found that lipidated HDL containing both apolipoprotein A-I (APOA1) and A-II (APOA2) promotes cholesterol efflux via the ATP-binding cassette transporter (ABCA1). In the current study, we directly added purified, lipid-free APOA2 to human plasma and found a dose-dependent increase in whole plasma cholesterol efflux capacity. APOA2 likewise increased the cholesterol efflux capacity of isolated HDL with the maximum effect occurring when equal masses of APOA1 and APOA2 coexisted on the particles. Follow-up …

Untargeted Lipidomics Reveals Novel Hdl Metabotypes And Lipid-Clinical Correlates, Peer W. F. Karmaus, Scott M. Gordon, Marcus Y. Chen, Alison A. Motsinger-Reif, Rodney W. Snyder, Timothy R. Fennell, Suramya Waidyanatha, Reshan A. Fernando, Alan T. Remaley, Michael B. Fessler

Saha Cardiovascular Research Center Faculty Publications

Plasma high-density lipoprotein (HDL), originally studied for its role in lipid transport, is now appreciated to have wide-ranging biological functions that become defective during disease. While >200 lipids have collectively been detected in HDL, published HDL lipidomic analyses in different diseases have commonly been targeted to prespecified subsets of lipids. Here, we report the results of untargeted lipidomic analysis of HDL isolated from 101 subjects referred for computed tomographic coronary imaging for whom multiple additional clinical and lipoprotein metadata were measured. Unsupervised clustering of the total HDL lipidome revealed that the subjects fell into one of two discrete groups, herein …

Diabetes Screening Among Women With Polycystic Ovary Syndrome: A Descriptive Study Of Commercial Claims, 2011–2019, Jacklyn Vollmer, W. Jay Christian, Mary E. Lacy

UK CARES Faculty Publications

Background Polycystic ovary syndrome (PCOS) is a hormonal disorder that affects 6–12% of United States women of reproductive age. Because women with PCOS are at an increased risk of developing type 2 diabetes, clinical practice guidelines from a number of organizations (e.g. American Diabetes Association, American College of Obstetricians and Gynecologists, US Preventive Services Task Force) recommend that individuals with PCOS are routinely screened for diabetes. Guidelines further indicate that an oral glucose tolerance test (OGTT) should be used for diabetes screening in women with PCOS as opposed to an A1C or fasting plasma glucose test. The purpose of this …

Estrogen Signaling Regulates The Sex Difference In Resynchronization To Abrupt Shifts Of The Light-Dark Cycle In A Mouse Model Of Jet Lag, Maria Venegas

Theses and Dissertations--Biology

The circadian system coordinates 24-hour cycles of internal biological processes with the environmental light-dark cycle. Abrupt shifts in the timing of the light-dark cycle misalign internal circadian clocks with the environment and cause jet lag until resynchronization occurs. The objective of this study was to investigate the mechanisms underlying sex differences in jet lag in mice. Female mice resynchronized faster than male mice to 6-hour advances and delays of the light-dark cycle, which mimicked eastward and westward travel, respectively. Circulating estradiol was necessary for rapid resynchronization in female mice since ovariectomized females resynchronized slower than mice treated with estradiol. We …

Impact Of Short-Distance Road Transportation On Horse Health, Erica Jacquay

Theses and Dissertations--Veterinary Science

Horses are regularly transported across the United States; however, the reasons for travel, trip lengths, and management practices are not well characterized. While long distance transportation has been associated with increased incidences of health-related problems, the impact of short distance transportation on horse health is less understood. Notably, aged horses ( > 15 years) have an altered immune response following short-distance transportation, but this has yet to be compared to young horses. It is also unknown whether transportation stress would alter endocrine responses of horses with metabolic disorders, such as insulin dysregulation (ID) or pituitary pars intermedia dysfunction (PPID).

The objectives …

Regulated Translocation Of Neutral Sphingomyelinase-2 To The Plasma Membrane Drives Insulin Resistance In Steatotic Hepatocytes, Salim S. El-Amouri, Alexander A. Karakashian, Erhard Bieberich, Mariana N. Nikolova‑Karakashian

Markey Cancer Center Faculty Publications

Abstract Obesity-associated diabetes is linked to the accumulation of ceramide in various organs, including the liver. The exact mechanisms by which ceramide contributes to diabetic pathology are unclear, but one proposed scenario is that ceramide accumulation may inhibit insulin signaling pathways. It is unknown however whether the excess ceramide is generated proximal to the insulin receptor, that is, at the plasma membrane (PM), where it could affect the insulin signaling pathway directly, or the onset of insulin resistance is due to ceramide- induced mitochondrial dysfunction and/or lipotoxicity. Using hepatic cell lines and primary cultures, gain- and loss- of function approach, …

Fructose Induced Khk-C Can Increase Er Stress Independent Of Its Effect On Lipogenesis To Drive Liver Disease In Diet-Induced And Genetic Models Of Nafld, Se-Hyung Park, Robert N. Helsley, Taghreed Fadhul, Jennifer L. S. Willoughby, Leila Noetzli, Ho-Chou Tu, Marie H. Solheim, Shiho Fujisaka, Hui Pan, Jonathan M. Dreyfuss, Joanna Bons, Jacob Rose, Christina D. King, Birgit Schilling, Aldons J. Lusis, Calvin Pan, Manoj Gupta, Rohit N. Kulkarni, Kevin Fitzgerald, Philip A. Kern, Senad Divanovic, C. Ronald Kahn, Samir Softic

Saha Cardiovascular Research Center Faculty Publications

Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome, and is estimated to affect one billion individuals worldwide. An increased intake of a high-fat diet (HFD) and sugar-sweetened beverages are risk-factors for NAFLD development, but how their combined intake promotes progression to a more severe form of liver injury is unknown. Here we show that fructose metabolism via ketohexokinase (KHK) C isoform leads to unresolved endoplasmic reticulum (ER) stress when coupled with a HFD intake. Conversely, a liver-specific knockdown of KHK in mice consuming fructose on a HFD is adequate to improve the NAFLD activity score and …

Differential Inhibition Of Anaplerotic Pyruvate Carboxylation And Glutaminolysis-Fueled Anabolism Underlies Distinct Toxicity Of Selenium Agents In Human Lung Cancer, Teresa W-M Fan, Jason Winnike, Ahmad Al-Attar, Alex C. Belshoff, Pawel Lorkiewicz, Jin Lian Tan, Min Wu, Richard M. Higashi, Andrew N. Lane

Markey Cancer Center Faculty Publications

Past chemopreventive human trials on dietary selenium supplements produced controversial outcomes. They largely employed selenomethionine (SeM)-based diets. SeM was less toxic than selenite or methylseleninic acid (MSeA) to lung cancer cells. We thus investigated the toxic action of these Se agents in two non-small cell lung cancer (NSCLC) cell lines and ex vivo organotypic cultures (OTC) of NSCLC patient lung tissues. Stable isotope-resolved metabolomics (SIRM) using 13C6-glucose and 13C5,15N2-glutamine tracers with gene knockdowns were employed to examine metabolic dysregulations associated with cell type- and treatment-dependent phenotypic changes. Inhibition of key anaplerotic processes, pyruvate carboxylation (PyC) and glutaminolysis were elicited by …

Serum Amyloid A Augments The Atherogenic Effects Of Cholesteryl Ester Transfer Protein, Ailing Ji, Andrea C. Trumbauer, Victoria P. Noffsinger, Frederick C. De Beer, Nancy R. Webb, Lisa R. Tannock, Preetha Shridas

Saha Cardiovascular Research Center Faculty Publications

Serum amyloid A (SAA) is predictive of CVD in humans and causes atherosclerosis in mice. SAA has many proatherogenic effects in vitro. However, HDL, the major carrier of SAA in the circulation, masks these effects. The remodeling of HDL by cholesteryl ester transfer protein (CETP) liberates SAA restoring its proinflammatory activity. Here, we investigated whether deficiency of SAA suppresses the previously described proatherogenic effect of CETP. ApoE¡/¡ mice and apoE¡/¡ mice deficient in the three acute-phase isoforms of SAA (SAA1.1, SAA2.1, and SAA3; “apoE¡/¡ SAA-TKO”) with and without adeno-associated virus-mediated expression of CETP were studied. There was no effect of …

Life Stressors And Immune Aging: Protective Effects Of Cognitive Reappraisal, Rebecca G. Reed, Steven R. Presnell, Ahmad Al-Attar, Charles T. Lutz, Suzanne C. Segerstrom

Markey Cancer Center Faculty Publications

Stressful life events may accelerate aspects of immune aging, but habitual use of an adaptive emotion regulation strategy, cognitive reappraisal, may attenuate these effects. This study examined whether cognitive reappraisal moderates the associations between life stressor frequency and stressor desirability on aspects of immune aging, including late-differentiated CD8+ T and natural killer (NK) cells and inflammatory markers (IL-6, TNF-α, and CRP), both between and within people in a longitudinal sample of 149 older adults (mean age = 77.8, range: 64–92 years). Participants reported stressful life events, use of cognitive reappraisal, and provided blood semiannually for up to 5 years to …

The Importance Of Translationally Evaluating Steroid Hormone Contributions To Substance Use, Erin E. Maher, Ashley Strzelecki, Jessica J. Weafer, Cassandra D. Gipson

Markey Cancer Center Faculty Publications

Clinically, women appear to be more susceptible to certain aspects of substance use disorders (SUDs). The steroid hormones 17β-estradiol (E2) and progesterone (Pg) have been linked to women-specific drug behaviors. Here, we review clinical and preclinical studies investigating how cycling ovarian hormones affect nicotine-, cocaine-, and opioid-related behaviors. We also highlight gaps in the literature regarding how synthetic steroid hormone use may influence drug-related behaviors. In addition, we explore how E2 and Pg are known to interact in brain reward pathways and provide evidence of how these interactions may influence drug-related behaviors. The synthesis of this review demonstrates the critical …

Increasing Efficiency Of Finishing Beef Production: Strategies To Optimize Starch Digestion, Improve Flake Quality, And Reduce Methane Emissions, Ronald J. Trotta

Theses and Dissertations--Animal and Food Sciences

To continue to meet the demands of increasing food production and environmental sustainability, new strategies are needed to enhance the efficiency of finishing cattle production. A review of the literature identified several nutritional and physiological constraints that limit the ability for cattle to digest starch and absorb glucose from the small intestine. Comparative sequencing analyses revealed a missing region of the sucrase-isomaltase protein which could affect the capacity for starch digestion in cattle. Post-flaking sampling and handling recommendations were generated based on a series of experiments to improve estimates of starch availability and flaking consistency for commercial feedlots and laboratories. …

Estrogen Regulation Of Daily Metabolic Rhythms In Female Mice, Oluwabukola Omotola

Theses and Dissertations--Biology

Circadian rhythms are approximately 24-hour cycles of behavior, physiology, and gene expression. In mammals, these circadian rhythms are generated by clocks located in nearly every tissue in the body. The function of circadian clocks is to synchronize physiology and behavior with environmental cycles such as the light-dark cycle. After menopause, when circulating levels of estrogens are very low, women are more susceptible to obesity comorbidities such as metabolic syndrome and cardiovascular disease, suggesting that estrogens regulate these processes. Estrogens could protect females from metabolic dysfunction by regulating circadian rhythms. Consumption of diets that are high in fat contribute to obesity. …

Rediscovering The Axolotl As A Model For Thyroid Hormone Dependent Development, Anne Crowner, Shivam Khatri, Dana Blichmann, S. Randal Voss

Neuroscience Faculty Publications

The Mexican axolotl (Ambystoma mexicanum) is an important model organism in biomedical research. Much current attention is focused on the axolotl's amazing ability to regenerate tissues and whole organs after injury. However, not forgotten is the axolotl's equally amazing ability to thwart aspects of tissue maturation and retain juvenile morphology into the adult phase of life. Unlike close tiger salamander relatives that undergo a thyroid hormone regulated metamorphosis, the axolotl does not typically undergo a metamorphosis. Instead, the axolotl exhibits a paedomorphic mode of development that enables a completely aquatic life cycle. The evolution of paedomorphosis allowed axolotls …

Responses Of Bovine Pituitary Transcriptome Profiles To Consumption Of Toxic Tall Fescue And Forms Of Selenium In Vitamin-Mineral Mixes, Qing Li

Theses and Dissertations--Animal and Food Sciences

The first goal of the current research was to determine whether gene expression profiles differed between whole pituitaries of growing beef steers grazing pastures containing high (HE) or low (LE) amounts of toxic endophyte-infected tall fescue. The global (microarray analysis) and selected targeted (RT-PCR) mRNA expression patterns of pituitaries collected from beef steers (BW = 266 ± 15.5 kg) that had been randomly assigned to undergo summer-long grazing (89 to 105 d) of either HE (0.52 ppm ergot alkaloids) or LE (< 0.03 ppm ergot alkaloids) pastures were compared. Gene expression data were subjected to one-way ANOVA. The pituitaries of HE steers had 542 differentially expressed genes, and the pattern of altered gene expression was dependent on treatment. Targeted RT-PCR analysis corroborated these findings, including decreased expression of DRD2, PRL, POU1F1, GAL, and VIP and that of POMC and PCSK1, respectively. Canonical pathway analysis (Integrated Pathway Analysis, IPA) identified HE-dependent alteration in signaling of additional pituitary-derived hormones, including growth hormone and GnRH. In conclusion, consumption of endophyte-infected tall fescue alters the pituitary transcriptome profiles of steers in a manner consistent with their negatively affected physiological parameters. The second goal of this project was to test the hypothesis that sodium selenite (ISe), SEL-PLEX (OSe), vs. a 1:1 blend (MIX) of ISe and OSe in a basal vitamin-mineral (VM) mix would differentially alter pituitary transcriptome profiles in growing beef steers (BW = 183 ± 34 kg) commonly grazing an endophyte-infected tall fescue (HE) pasture. Steers were randomly selected from herds of fall-calving cows grazing HE pasture and consuming VM mixes that contained 35 ppm Se as either ISe, OSe, or MIX forms. Steers were weaned, depleted of Se for 98 d, and subjected to summer-long common grazing of a 10.1 ha HE pasture containing 0.51 ppm ergot alkaloids. Steers were assigned (n = 8) to the same Se-form treatments on which they were raised. Selenium treatments were administered by daily top-dressing 85 g of VM mix onto 0.23 kg soyhulls, using in-pasture Calan gates. Pituitaries were collected at slaughter and changes in global (microarray) and selected (RT-PCR) mRNA expression patterns determined. The effects of Se treatment on relative gene expression were subjected to one-way ANOVA. The form of Se affected the expression of 542 annotated genes. Integrated Pathway Analysis found a canonical pathway network between prolactin and POMC/ACTH/ α-MSH synthesis-related proteins, and that mitochondrial dysfunction was a top-affected canonical pathway. Targeted RT-PCR analysis found that the relative abundance of mRNA encoding prolactin and POMC/ACTH/ α-MSH synthesis-related proteins was affected by the form of Se, as were mitochondrial dysfunction-related proteins OSe steers appeared to have a greater prolactin synthesis capacity vs. ISe steers through decreased dopamine receptor D2 signaling, whereas MIX steers had a greater prolactin synthesis capacity and release potential by increasing TRH concentrations than ISe steers. OSe steers also had a greater ACTH and α-MSH synthesis potential than ISe steers. We conclude that form of Se in VM mixes affected genes responsible for prolactin and POMC/ACTH/α-MSH synthesis, and mitochondrial function in pituitaries of growing beef steers commonly grazing an HE pasture. The third goal was to test the hypothesis that sodium selenite (ISe), SEL-PLEX (OSe), vs. a 1:1 blend (MIX) of ISe and OSe in a basal vitamin-mineral (VM) mix would differentially alter selenoprotein profiles in pituitaries and livers of growing beef steers commonly grazing an endophyte-infected tall fescue (HE) pasture (i.e., the same steers used in Goal 2). The effects of Se treatment on relative gene expression were subjected to one-way ANOVA. The mRNA content of 6 selenoproteins in the pituitary was affected by Se treatments, along with two selenoprotein P receptors, whereas the expression of two selenoproteins was altered in the liver. We conclude that the change in selenoprotein gene expression in pituitaries indicates that OSe steers have a greater potential capacity to manage against oxidative damage, maintain cellular redox balance, and have a better quality control of protein-folding in their pituitaries than ISe steers. The change in selenoprotein gene expression by the liver indicates that MIX steers have a greater redox signaling capacity and capacity to manage oxidative damage than ISe steers.

The Impact Of Insulin Dysregulation On Protein Metabolism In Horses, Caroline Margot Marcelle Loos

Theses and Dissertations--Animal and Food Sciences

Insulin plays a vital role in whole-body metabolism and provides a major anabolic stimulus for cellular signaling pathways, including those involved in the metabolism of glucose and protein. Consequently, insulin dysregulation (ID) is known to alter molecular signal transduction in insulin-sensitive tissues such as skeletal muscle, thereby disrupting glucose metabolism and compromising protein synthetic capacity. Our first objective was to induce ID in healthy horses by administering dexamethasone (DEX), a potent glucocorticoid, for 21 days. We evaluated the effects on insulin-stimulated muscle protein signaling components involved in the mammalian target of rapamycin (mTOR) pathway. DEX-induced ID reduced insulin-stimulated activation of …

Primary Upper Urinary Tract Small Cell Carcinoma: A Case Series And Literature Review, Patrick J. Hensley, Amul A. Bhalodi, Shubham Gupta

Urology Faculty Publications

Background: Primary upper urinary tract small cell carcinoma (SCC) is exceedingly rare with < 30 cases reported in the literature. Little is known about the incidence, diagnosis, treatment, and outcomes in these patients. We present a series of three patients with primary upper tract SCC.

Case Presentation: Patient 1 is an 89-year-old Caucasian male who presented with hydroureteronephrosis and a mass in the proximal right ureter. Biopsy revealed SCC. Without further intervention, the patient died 2 months after his diagnosis. Patient 2 is a 67-year-old Caucasian female who underwent left laparoscopic nephroureterectomy for primary distal ureteral SCC, pT4N1M0. She developed lymphadenopathy and completed external beam radiation to the pelvis and four courses of cisplatin-based chemotherapy. She died from metastatic disease 7 months after diagnosis. Patient 3 is a 45-year-old female who underwent …

High-Fat Feeding Does Not Disrupt Daily Rhythms In Female Mice Because Of Protection By Ovarian Hormones, Brian T. Palmisano, John M. Stafford, Julie S. Pendergast

Biology Faculty Publications

Obesity in women is increased by the loss of circulating estrogen after menopause. Shift work, which disrupts circadian rhythms, also increases the risk for obesity. It is not known whether ovarian hormones interact with the circadian system to protect females from obesity. During high-fat feeding, male C57BL/6J mice develop profound obesity and disruption of daily rhythms. Since C57BL/6J female mice did not develop diet-induced obesity (during 8 weeks of high-fat feeding), we first determined if daily rhythms in female mice were resistant to disruption from high-fat diet. We fed female PERIOD2:LUCIFERASE mice 45% high-fat diet for 1 week and measured …

The Effects Of Perinatal Oxycodone Exposure On The Stress Axis And Neurobehavior, Thitinart Sithisarn

Theses and Dissertations--Physiology

Opiate addiction is now a major public health problem. Pregnant women continue to use opiates during gestation; up to 5.4% of pregnant women report using illicit drugs during pregnancy. Previous studies have shown that perinatal insults and exposure to opiates such as morphine in utero can affect the development of the hypothalamic-pituitary-adrenal (HPA)-axis of the offspring and are associated with higher risk of developing neurobehavioral problems. Oxycodone, a semisynthetic putative kappa opioid receptor and partial mu opioid receptor agonist is now one of the most frequently abused pain killers during pregnancy, however limited data are available regarding whether and how …

Intrinsic And Extrinsic Regulation Of Pineal Melatonin Rhythms, Ye Li

Theses and Dissertations--Biology

Circadian rhythm is a biological rhythm with period of about 24 hours. Circadian rhythm is universal in phyla from bacteria to mammals and exists in different level from gene expression to behavior. Circadian system consists of three components: 1) a self-sustained oscillator; 2) an input pathway which can alter the phase of the oscillator; and 3) an output such as gene expression, enzyme activity, hormone production, heart rate, body temperature or locomotor activities. The way the oscillator regulates its outputs is complicated, in that on one hand usually the oscillator is not the only factor affecting the outputs, and on …

Expression Of Borderline Personality Disorder Symptoms Across The Ovulatory Cycle: A Multilevel Investigation, Tory A. Eisenlohr-Moul

Theses and Dissertations--Psychology

Borderline Personality Disorder (BPD) is a disabling condition characterized by chronic emotion dysregulation and behavioral impulsivity. Prospective studies that test proposed mechanisms of within-person change in BPD hold the key to improving symptom predictability and control in this disorder. A small body of evidence suggests that fluctuations in estradiol such as those occurring naturally at ovulation during the monthly female reproductive cycle may increase symptoms in women with BPD (DeSoto et al., 2003). Furthermore, there is preliminary evidence that both self-esteem and feelings of social rejection are highest at ovulation, when estradiol peaks (Durante and Hill, 2009; Eisenlohr-Moul et al., …